Numerous clinical studies have suggested a link between loss of sensory function in the inner ear and the development of Alzheimer?s disease, but the biological basis of this association is not clear. The neurodegeneration that occurs in Alzheimer?s disease (AD) is thought to be caused by aberrant processing and clustering of protein fragments derived from amyloid precursor protein (APP) and the microtubule-associated protein Tau. Certain identified mutations in APP and Tau are also known to greatly increase the risk of developing AD. The study of AD-related degeneration in mouse models presents certain challenges. Because of small differences in the sequences of AD-associated genes in humans vs. rodents, mice do not normally develop AD- like neurodegeneration. However, a number of transgenic knock-in lines that express human forms of these AD- associated gene mutations have been created, facilitating the study of amyloid- and Tau-mediated pathology. We are requesting an administrative supplement to our R01 grant, ?Role of the Innate Immune System in the Survival of Auditory Neurons?, in order to test for cellular degeneration in the inner ears and auditory brainstem nuclei of a widely-used mouse model of Alzheimer?s disease. Our pilot data show that both APP and Tau are highly expressed by hair cells and afferent neurons of the inner ear, raising the possibility that mutated forms of these proteins might promote age-related loss of hearing and balance function. It is further possible that the loss of sensory function in such mice makes neurons of the CNS more susceptible to AD pathology and degeneration. One set of proposed experiments will examine whether there is increased loss of spiral ganglion and vestibular ganglion neurons in AD-model mice, and whether the sensory ganglia of these mice contain amyloid plaques and increased numbers of inflammatory cells. Prior studies from our labs have also shown that once the auditory system has matured, the survival of the neurons in the cochlear nucleus is not dependent on maintained sensory input. We hypothesize that expression of AD-associated genes will make these neurons become vulnerable to the loss of synaptic input from the ear, such as routinely occurs with aging. A second set of experiments will test this hypothesis by determining if the expression of AD-associated mutations causes the neurons of the ventral cochlear nucleus (VCN) to show increased vulnerability to loss of sensory input. Such an event might result in a cascade of peripheral and central events leading to increased cognitive and sensory motor decline. The outcome of these studies may help explain the link between hearing loss and the devilment of Alzheimer?s pathology.